Therapeutic agents useful for treating inflammatory diseases

Abstract

PCT No. PCT/EP92/02899 Sec. 371 Date Jun. 3, 1994 Sec. 102(e) Date Jun. 3, 1994 PCT Filed Dec. 12, 1992 PCT Pub. No. WO93/13075 PCT Pub. Date Jul. 8, 1993This invention relates to compounds of formula I and pharmaceutically acceptable salts thereof represent hydrogen, halo, alkyl, alkoxy, phenoxy, phenyl, alkoxycarbonyl, -NR13R14, halogenated alkoxy, halogenated alkyl, benzyloxy, hydroxy, hydroxyalkyl, (C2-6 alkoxycarbonyl)vinyl, -S(O)nR7, carbamoylalkyl, alkoxycarbonylalkyl, -CONR11R12, or R1 and R2 together with the phenyl ring represent a naphthyl group; R4 and R5 independently represent hydrogen, alkyl, phenyl or together with the carbon atom represent C3-6 cycloalkyl; R6 represents hydrogen, alkyl or omega -hydroxy alkyl; A represents C2-9 alkylene; R8 represents hydrogen, alkyl, halo, alkoxy, hydroxyalkyl, benzyl or phenyl; R9 and R10 independently represent hydrogen, alkyl, halo, alkoxy, phenyl, hydroxyalkyl, alkoxycarbonyl, nitro, -NR30R31, alkanoyloxyalkyl, or aminomethyl; which are antiinflammatory and antiallergic agents. Compositions containing these compounds and processes to make them are also disclosed.

We claim: 
     
       1. Compounds of formula II ##STR38## and pharmaceutically acceptable salts thereof in which R 1  represents halo, a C 1-4  alkyl group, a C 2-4  alkoxy group, phenoxy, phenyl, a C 2-4  alkoxycarbonyl group, a perhalo C 1-2  alkoxy group, a perhalo C 1-2  alkyl group, benzyloxy, an amino group of formula NR 13  R 14  (in which R 13  and R 14  independently represent hydrogen or a C 1-4  alkyl group), a (C 2-4  alkoxycarbonyl)vinyl group, a C 2-6  alkoxycarbonyl C- 1-2  alkyl group or R 1  and R 2  together with the phenyl ring to which they are attached represent a naphthyl group; R 2  and R 3  independently represent hydrogen, halo, a C 1-4  alkyl group, a C 1-4  alkoxy group, a perhalo C 1-2  alkyl group, or hydroxy;   R 4  and R 5  independently represent hydrogen, a C 1-4  alkyl group, phenyl or R 4  and R 5  together with the carbon atom to which they are attached represent a C 3-6  cycloalkyl group;   R 6  represents hydrogen or a C 1-3  alkyl group;   A represents ethylene [trimethylene, tetramethylene, 1,1-dimethylethylene or heptamethylene];   R 8  represents hydrogen, a C 1-4  alkyl group, phenyl or benzyl; and   R 9  and R 10  independently represent hydrogen, a C 1-4  alkyl group, halo, a C 1-4  hydroxyalkyl group, a C 2-6  alkoxycarbonyl group, nitro, or a C 1-6  alkanoyloxy C 1-2  alkyl group.   
     
     
       2. Compounds according to claim 1 in which R 1  represents bromo, chloro, methyl, ethyl, t-butyl, butoxy, phenoxy, phenyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, dimethylamino, trifluoromethoxy, trifluoromethyl, benzyloxy, 2-ethoxycarbonylvinyl or R 1  and R 2  together with the phenyl ring to which they are attached represent a naphthyl group. 
     
     
       3. Compounds according to claim 1 in which R 2  represents hydrogen, 3-chloro, 2-chloro, 3-fluoro, 2-methyl, 3-methyl, 2-methoxy, 2-ethoxy, 2-hydroxy or 3-trifluoromethyl and R 3  represents hydrogen, 2-chloro or 3-chloro. 
     
     
       4. Compounds according to claim 1 in which R 6  represents hydrogen or methyl. 
     
     
       5. Compounds according to claim 1 in which R 8  represents hydrogen, methyl, ethyl, isopropyl, phenyl or benzyl. 
     
     
       6. Compounds according to claim 1 in which R 9  and R 10  independently represent hydrogen, methyl, chloro, hydroxymethyl, ethoxycarbonyl, nitro or acetoxymethyl. 
     
     
       7. A compound of formula II as claimed in claim 1 which is N-[1-(4-Chlorophenyl)-1-methylethyl]-3-(imidazol-1-yl)-propylamine and pharmaceutically acceptable salts thereof. 
     
     
       8. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula II of claim 1 in combination with pharmaceutically acceptable diluent or carrier. 
     
     
       9. A pharmaceutical composition according to claim 8, formulated as a tablet. 
     
     
       10. A pharmaceutical composition according to claim 8 suitable for inhalation via the mouth and/or nose. 
     
     
       11. A pharmaceutical composition according to claim 8 suitable for topical administration. 
     
     
       12. A compound selected from the group consisting of: N-[1-(2,4-Dichlorophenyl)ethyl]-3-(imidazol-1-yl)-propylamine;   N-[1-(4-Benzyloxyphenyl)ethyl]-3-(imidazol-1-yl)propylamine;   N-[1-(4-Chloro-3-trifluoromethylphenyl)ethyl]-3-(imidazol-1-yl) propylamine;   N-[1-(4-Chloro -3-fluorophenyl)ethyl]-3-(imidazol-1-yl)propylamine;   3-(Imidazol-1-yl)-N-[1-(4-trifluoromethylphenyl)ethyl]propylamine;   N-[1-(4-Chloro -3-methylphenyl)ethyl]-3-(imidazol-1-yl)propylamine;   N-[1-(2,3,4-Trichlorophenyl)ethyl]-3-(imidazol-1-yl)propylamine;   3-(Imidazol-1-yl)-N-[1-(4-phenoxyphenyl)ethyl]propylamine;   N-[1-(4-Tert-butylphenyl)ethyl]-3-(imidazol-1-yl)propylamine;   N-[1-(4-Butoxyphenyl)ethyl]-3-(imidazol-1-yl)propylamine;   3-(Imidazol-1-yl)-N-[1-(4-trifluoromethoxyphenyl)ethyl]propylamine;   N-[1-(4-Chlorophenyl)ethyl]-3-(4,5-dimethylimidazol-1-yl) propylamine;   N-[1-(4-Chlorophenyl)ethyl]-3-(2-phenylimidazol-1-yl)propylamine;   N-[1-(4-Chlorophenyl)ethyl]-3-(2-methylimidazol-1-yl)propylamine;   N-[α-(4-chlorophenyl)benzyl]-3-(imidazol-1-yl)propylamine;   5-Chloro-2-{1-[3-(imidazol-1-yl)propylamino]ethyl}phenol;   N-[1-(4-Chlorophenyl)propyl]-3-(imidazol-1-yl)propylamine;   N-[1-(4-Chlorophenyl)ethyl]-3-(2,4-dimethylimidazol-1-yl)propylamine;   3-(2-Benzyl-4-methylimidazol-1-yl)-N-[1-(4-chlorophenyl)ethyl]propylamine;   3-(2-Benzyl-5-methylimidazol-1-yl)-N-[1-(4-chlorophenyl)ethyl]propylamine;   N-[1-(4-Chlorophenyl)ethyl]-3-(4-methyl-2-phenylimidazol-1-yl)propylamine;   N-[1-(4-Chlorophenyl)ethyl]-3-(5-methyl-2-phenylimidazol-1-yl)propylamine;   N-Benzhydryl -3-(imidazol-1-yl)propylamine;   N-(3,4-Dichlorobenzyl)-3-(imidazol-1-yl)propylamine;   3-(Imidazol-1-yl)-N-(4-phenoxybenzyl)propylamine;   N-(4-Chlorobenzyl)-3-(2-methylimidazol-1-yl)propylamine;   N-(4-Chlorobenzyl)-3-(4-methylimidazol-1-yl)propylamine;   N-(4-Chlorobenzyl)-3-(5-methylimidazol-1-yl)propylamine;   N-(4-Chlorobenzyl)-3-(4,5-dimethylimidazol-1-yl)propylamine;   N-(4-Chlorobenzyl)-3-(5-methyl-2-phenylimidazol-1-yl)propylamine;   N-(4-Chlorobenzyl)-3-(4-methyl -2-phenylimidazol-1-yl)propylamine;   Methyl 4-[3-(2-methylimidazol-1-yl)propylaminomethyl]benzoate;   3-(Imidazol-1-yl)-N-(4-methoxy-2,6-dimethylbenzyl)propylamine;   Ethyl 4-[3-(2-methylimidazol-1-yl)propylaminomethyl]cinnamate;   (-) N-[1-(4-Chlorophenyl)ethyl]-3-(imidazol-1-yl)propylamine;   N-[1-(4-Chlorophenyl)ethyl]-3-(2-ethylimidazol-1-yl)propylamine;   N-[1-(4-Chlorophenyl)ethyl]-3-(4-methylimidazol-1-yl)propylamine;   N-[1-(4-Chlorophenyl)ethyl]-3-(5-methylimidazol-1-yl)propylamine;   (+) N-[1-(4-Chlorophenyl)ethyl]-3-(imidazol-1-yl)propylamine;   N-[1-(4-Chlorophenyl)-1-methylethyl]-3-(imidazol-1-yl)propyiamine;   N-[1-(4-Chlorophenyl)-1-methylethyl]-3-(2-methylimidazol-1-yl)propylamine;   N-(4-Chlorobenzyl)-3-(4,5-dichioroimidazol-1-yl)propylamine;   N-[1-(4-Chlorophenyl)ethyl]-3-(2-isopropylimidazol-1-yl)propylamine;   N-[1-(4-Chlorophenyl)ethyl]-3-(2,4,5-trimethylimidazol-1-yl)propylamine;   N-[1-(4-Chlorophenyl)ethyl]-3-(4,5-dichloroimidazol-1-yl)propylamine;   N-[1-(4-Chlorophenyl)-1-methylethyl]-3-(4-methylimidazol-1-yl)propylamine;   N-[1-(4-Chlorophenyl)-1-methylethyl]-3-(5-methylimidazol-1-yl)propylamine;   N-[1-(4-Chlorophenyl)-1-methylethyl]-3-(4,5-dimethylimidazol-1-yl)propylamine;   N-(4-Chlorobenzyl)-3-(2-isopropylimidazol-1-yl)propylamine;   N-(4-Chlorobenzyl)-3-(2-ethylimidazol-1-yl)propylamine;   3-(2-Methylimidazol-1-yl)-N-[1-methyl-1-(p-tolyl)ethyl]propylamine;   3-(Imidazol-1-yl)-N-[1-methyl-1-(p-tolyl)ethyl]propylamine;   1-(4-Chlorophenyl)-1-ethyl]-3'-(imidazol-1-yl)dipropylamine;   1-{3-[1-(4-Chlorophenyl)-1-methylethylamino]propyl}imidazol-4-yl-methanol;   N-[1-(4-Biphenyiyl)-1-methylethyl]-3-(imidazol-1-yl)propylamine;   N-[1-(4-Chlorophenyl)cycloprop-1-yl]-3-(imidazol-1-yl)propylamine;   N-[1-(2-Naphthyl)-1-methylethyl]-3-(imidazol-1-yl)propylamine;   1-{3-[1-(3,4-Dichlorophenyl)-1-methylethylamino]propyl}imidazol-5-yl-methanol;   1-{3-[1-(4-Biphenylyl)-1-methylethylamino]propyl}imidazol-4-yl-methanol;   N-[1-(4-Benzyloxyphenyl)-1-methylethyl]-3-(imidazol-1-yl)propylamine;   N-(4-Chlorobenzyl)-3-(2,4-dimethylimidazol-1-yl)propylamine;   3-(2-Benzyl-4-methylimidazol-1-yl)-N-(4-chlorobenzyl)propylamine;   Propyl 4-[3-(2-methylimidazol-1-yl)propylaminomethyl]benzoate;   1-{3-[1-(4-Chlorophenyl)-1-methylethylamino]propyl}-5-methylimidazol-4-ylmethyl acetate; and pharmaceutically acceptable salts thereof in the form of individual enantiomers, racemates or other mixtures of enantiomers.     
     
     
       13. A method of treating inflammatory and/or allergic diseases in a mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula I ##STR39## and pharmaceutically acceptable salts thereof in which R 1 , R 2  and R 3  independently represent hydrogen, halo, a C 1-6  alkyl group, a C 1-6  alkoxy group, phenoxy (optionally substituted by a C 1-6  alkyl group, a C 1-4  alkoxy group or halo), phenyl (optionally substituted by a C 1-4  alkylgroup, a C 1-4  alkoxy group or halo), a C 2-6  alkoxycarbonyl group, an amino group of formula --NR 13  R 14  (in which R 13  and R 14  are indeptendently hydrogen or a C 1-4  alkyl group or R 13  and R 14  together with he nitrogen atom to which they are attached represent a pyrrolidine ring, a morpholine ring or a piperidine ring), a halogenated C 1-4  alkoxy group, a halogenated C 1-4  alkyl group, benzyloxy (optionally substituted by a C 1-4  alkyl group, a C 1-4  alkoxy group or halo), hydroxy, a C 1-4  hydroxyalky group, a (C 2-6  alkoxycarbonyl)vinyl group; a group of formula --S(O) n  R 7  (in which R 7  represents a C 1-4  alkyl group and n is 0, 1 or 2), a C 2-4  -carbamoylalkyl group, a C 2-6  alkoxycarbonyl C 1-2  alkyl group, a carbamoyl group of formula --CONR 11  R 12  (in which R 11  and R 12  are independently hydrogen or a C 1-6  alkyl group) or R 1  and R 2  together with the phenyl ring to which they are attached represent a naphthyl group; R 4  and R 5  independently represent hydrogen, a C 1-4  alkyl group, phenyl (optionally substituted by a C 1-4  alkyl group, halo or a C 1-4  alkoxy group) or R 4  and R 5  together with the carbon atom to which they are attached represent a C 3-6  cycloalkyl group;   R 6  represents hydrogen, a C 1-4  alkyl group or an ω-hydroxy C 1-4  alkyl group;   A represents a C 2-9  alkylene group, which may be straight or branched;   represents hydrogen, a C 1-6  alkyl group, halo, a C 1-4  alkoxy group, a C 1 ∝ hydroxyalkyl group, phenyl (optionally substituted by a C 1-4  alkyl group, halo or a C 1-4  alkoxy group) or benzyl (optionally substituted by a C 1-4  alkyl group, halo or a C 1-4  alkoxy group);   R 9  and R 10  independently represent hydrogen, a C 1-6  alkyl group, halo, a C 1-4  alkoxy group, phenyl (optionally substituted by a C 1-4  alkyl group, halo or a C 1-4  alkoxy group), a C 1-4  hydroxyalkyl group, a C 2-6  alkoxycarbonyl group, nitro, an amino group of formula NR 30  R 31  (in which R 30  and R 31  independently represent hydrogen or a C 1-4  alkyl group), a C 1-6  alkanoyloxy C 1-4  alkylgroup, or an aminomethyl group;   with the provisos that 1) when A represents (CH 2 ) 2  and R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R 9  and R 10  represent hydrogen then R 8  does not represent hydrogen or 4-chloro, 2) when A represents (C 2 ) 5  and R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9  and R 10  represent hydrogen then R 8  does not represent methyl and 3) when R 1 , R 2 , R 3 , R 6  R 8 , R 9  and R 10  each represent hydrogen and A represents (CH 2 ) 2  then R 4  and R 5  are both methyl.   
     
     
       14. A method according to claim 13 wherein the disease is asthma.